Use of Calcitonin for the Treatment of RA

ABSTRACT

The present invention relates to a novel use of calcitonin in rheumatoid arthritis, and to methods of treating and/or preventing rheumatoid arthritis and conditions associated therewith in mammals, particularly humans. 
     In particular, a method is provided of preventing or/and treating rheumatoid arthritis in a patient in need thereof comprising administering to said patient a therapeutically effective amount of calcitonin, e.g. salmon calcitonin in free form or salt form, in a pharmaceutically acceptable oral delivery form, wherein the therapeutically effective amount of a calcitonin is delivered orally in a composition comprising the calcitonin and a delivery agent for calcitonin.

FIELD OF THE INVENTION

The present invention relates to a novel use of calcitonin in rheumatoidarthritis, and to methods of treating and/or preventing rheumatoidarthritis in mammals, particularly humans.

BACKGROUND OF THE INVENTION

Calcitonins, e.g. salmon, (Asu 1-7)-eel or human calcitonin, of theinvention are compounds which are long-chain polypeptide hormonessecreted by the parafollicular cells of the thyroid gland in mammals andby the ultimobranchial gland of birds and fish. Calcitonin is mainlyknown as a potent inhibitor of osteoclastic bone resorption, whichimplicates bone attachment of osteoclasts and enzymatic degradation.Furthermore, it was found that there are effects of Intranasal SalmonCalcitonin in Juvenile Idiopathic Arthritis in humans (Siamopoulou A. etal, 2001, Calcif Tissue Int 69: 25-30) and in the prevention of boneerosion and bone loss in rheumatoid arthritis in humans (Sileghem A.,1992, Annals of Rheumatic Diseases 51: 761-764). The degradative processassociates synthesis of various proteases and metalloproteinases,activation of inactive proenymes and inhibition of active enzymes(Leloup G, 1994, J Bone Miner Res, 9, 891-902). Calcitonin is known toinduce osteoclast retraction (Zheng M H, et al., 1992, Exper MolePathol, 57: 105-115) and to interfere at least with some steps of theenzymatic process of bone resorption (Einhom T A et al., 1991, ClinOrthop 262: 286-297). There are some reported studies on the effects ofcalcitonin on articular cartilage. In vitro, calcitonin was found tostimulate proteoglycan and collagen synthesis in animal epiphysealcartilage (Baxter et al., 1984, Endocrinology 114: 1196-1202) as well asin rabbit and human cartilage (Franchimont P, 1989, J Clin End Metab 69:259-266).

In accordance with the present invention, it has now surprisingly beenfound that oral delivery of calcitonin, e.g. salmon, (Asu 1-7)-eel orhuman calcitonin is useful in the prevention and treatment of rheumatoidarthritis in mammals, particularly humans. Said oral delivery ofcalcitonin surprisingly shows better results than other delivery routesand therefore is the delivery route of choice since reliably absorbed,convenient, relatively easy and generally painless, resulting in greaterpatient compliance relative to other modes of delivery.

Said oral delivery of calcitonin surprisingly shows better absorptionand then more suitable pharmacokinetic profile (PK profile) and lessvariability.

Rheumatoid arthritis (RA), a chronic, systemic, inflammatory autoimmunedisease, has as its primary target the synovial tissues. When thedisease is unchecked, it leads to substantial disability and prematuredeath. It affects approximately 0.8 percent of adults worldwide, is morecommon in women (by a ratio of 3 to 1), and has an earlier onset inwomen, frequently beginning in the childbearing years.

Joint damage occurs early in the course of rheumatoid arthritis; 30percent of patients have radiographic evidence of bony erosions at thetime of diagnosis, and this proportion increases to 60 percent by twoyears. The diagnosis cannot be established by a single laboratory testor procedure but is aided by the use of seven diagnostic criteria thatfavor clinical factors and, therefore, depend on the clinician's askinginsightful questions and recognizing the often-subtle early physicalfindings. The diagnostic criteria are the presence of morning stiffness,arthritis of three or more joint areas, arthritis of the hand joints,symmetric arthritis, rheumatoid nodules, elevated levels of serumrheumatoid factor, and radiographic changes. Many other syndromes,including self-limiting viral conditions lasting several weeks, mimicrheumatoid arthritis.

Rheumatoid arthritis is a disease characterised by inflammation andswelling of skeletal joints, especially the small joints of theextremities, leading to erosion and destruction of cartilage and bone.The present invention may be used to inhibit, halt or even reverse thecartilage and bone erosion and destruction, and to decrease the pain,associated with rheumatoid arthritis.

SUMMARY OF THE INVENTION

In accordance with the particular findings of the present invention,there is provided:

1.1 A method of preventing or/and treating rheumatoid arthritis in apatient in need thereof comprising administering to said patient atherapeutically effective amount of calcitonin, e.g. salmon calcitoninin free form or salt form, in a pharmaceutically acceptable oraldelivery form, wherein the therapeutically effective amount of acalcitonin is delivered orally in a composition comprising thecalcitonin and a delivery agent for calcitonin.1.2 A method of preventing or/and treating rheumatoid arthritis in apatient in need thereof comprising administering to said patient atherapeutically effective amount of calcitonin, e.g. salmon calcitoninin free form or salt form, in a pharmaceutically acceptable oraldelivery form, wherein the therapeutically effective amount of acalcitonin is delivered orally in a composition comprising thecalcitonin which is conjugated to a polymer molecule.1.3 A method of inhibiting inflammation of the joints in a patient inneed thereof comprising administering orally to said patient atherapeutically effective amount of calcitonin, e.g. salmon calcitoninin free form or salt form, in a pharmaceutically acceptable oraldelivery form;1.4 A method of inhibiting swelling of skeletal joints in a patient inneed thereof comprising administering orally to said patient atherapeutically effective amount of calcitonin, e.g. salmon calcitoninin free form or salt form, in a pharmaceutically acceptable oraldelivery form;1.5 A method of inhibiting, halting or even reversing the cartilage andbone erosion and destruction in a patient in need thereof comprisingadministering orally to said patient a therapeutically effective amountof calcitonin, e.g. salmon calcitonin in free form or salt form, in apharmaceutically acceptable oral delivery form;1.6 A method of decreasing pain, associated with rheumatoid arthritis ina patient in need thereof comprising administering orally to saidpatient a therapeutically effective amount of calcitonin, e.g. salmoncalcitonin in free form or salt form, in a pharmaceutically acceptableoral delivery form;1.7 A method as defined above, comprising co-administration of atherapeutically effective amount of calcitonin, e.g. salmon calcitoninin free form or salt form, in a pharmaceutically acceptable oraldelivery form, and a second drug substance. Suitable second drugsubstances may include a calcitonin of different origin, e.g. salmon,(Asu 1-7)-eel or human calcitonin, a calcitonin analogue or derivativethereof, COX-2 inhibitors, e.g. lumiracoxib (Prexige®), celecoxib(Celebrex®), rofecoxib (Vioxx®), valdecoxib (Bextra®), etoricoxib(Arcoxia®), or mixed COX-1 and COX-2 inhibitors, e.g. diclofenac,Etanercept, (Enbrel®), pain killers (e.g. Aspirin, Paracetamol), boneformers and bone antiresorbers.1.8 A method as defined above, comprising co-administration of atherapeutically effective amount of calcitonin, e.g. salmon calcitoninin free form or salt form, in a pharmaceutically acceptable oraldelivery form, and a second drug substance, said second drug substancebeing salmon, (Asu 1-7)-eel or human calcitonin, a calcitonin analogueor derivative thereof in free form or salt form.1.9 A method as defined above, comprising co-administration of atherapeutically effective amount of calcitonin, e.g. salmon calcitoninin free form or salt form, in a pharmaceutically acceptable oraldelivery form, and a second drug substance, said second drug substancebeing a COX-2 inhibitor e.g. lumiracoxib (Prexige®), celecoxib(Celebrex®), rofecoxib (Vioxx®), valdecoxib (Bextra®), etoricoxib(Arcoxia®), in free form or salt form.2. A method as defined above, comprising co-administration of atherapeutically effective amount of calcitonin, e.g. salmon calcitoninin free form or salt form, in a pharmaceutically acceptable oraldelivery form, and a second drug substance, said second drug substancebeing a mixed COX-1 and COX-2 inhibitors, e.g. diclofenac in free formor salt form.2.1 A method as defined above, comprising co-administration of atherapeutically effective amount of calcitonin, e.g. salmon calcitoninin free form or salt form, in a pharmaceutically acceptable oraldelivery form, and a second drug substance, said second drug substancebeing a pain killers (e.g. Aspirin, Paracetamol), in free form or saltform.2.2 A method as defined above, comprising co-administration of atherapeutically effective amount of calcitonin, e.g. salmon calcitoninin free form or salt form, in a pharmaceutically acceptable oraldelivery form, and a second drug substance, said second drug substancebeing Etanercept, (Enbrel®) in free form or salt form.Etanercept (Enbrel®) is a dimeric fusion protein consisting of theextracellular legand-binding portion of the human 75 kilodalton tumornecrosis factor receptor (TNFR). It is a anti TNF which bindsspecifically to TNF receptors and blocks its interaction with cellsurface TNF receptorsIn another aspect, the invention provides a particular dosage range fora calcitonin, e.g. salmon calcitonin, which is efficacious and welltolerated, i.e. safe for a patient to take. Preferred is a range between0.4 and 2.5 mg of salmon calcitonin for a patient, e.g. human, e.g. anaverage human of about 70 kg. More preferred are doses around 0.8 mg,e.g. between 0.6 and 1.2 mg. Also preferred are doses less than 1 mg buthigher than 0.4 mg. Even more preferred is a dose of about 0.6-0.8 mg,e.g. 0.8 mg. Most preferred is a dose of about 0.8 mg, e.g. between 0.8and 1.2 mg, administered once per day to a patient in need thereof.Pharmaceutical compositions comprising said doses according to theinvention are appropriate for oral delivery. The dosage regimen may beonce a day or twice a day, preferably one in the morning and one in theevening.2.3 A method of preventing or/and treating rheumatoid arthritis in apatient in need thereof comprising administering orally to said patienta pharmaceutical composition comprising between 0.4 and 2.5 mg,preferably between 0.6 and 1.2 mg of a calcitonin, e.g. salmoncalcitonin.2.4 The use of a calcitonin, e.g. salmon calcitonin, in the manufactureof a medicament for the treatment and/or prevention of rheumatoidarthritis, wherein said calcitonin is provided in a pharmaceuticalcomposition administered orally comprising between 0.4 and 2.5 mg,preferably between 0.6 and 1.2 mg of a calcitonin, e.g. salmoncalcitonin.2.5 A pharmaceutical composition for oral use in treating or/andpreventing rheumatoid arthritis comprising between 0.4 and 2.5 mg,preferably between 0.6 and 1.2 mg of a calcitonin, e.g. salmoncalcitonin.The terms “co-administration” or “combined administration” or the likeas utilized herein are meant to encompass administration of the selectedtherapeutic agents to a single patient, and are intended to includetreatment regimens in which the agents are not necessarily administeredby the same route of administration or at the same time.As alternative to the above the present invention also provides:2.6. A calcitonin, e.g. salmon, (Asu 1-7)-eel or human calcitonin infree form or salt form, in a pharmaceutically acceptable oral deliveryform, for use in any method as defined under 1.1 to 2.3 above; or2.7. A calcitonin, e.g. salmon, (Asu 1-7)-eel or human calcitonin infree form or salt form, in a pharmaceutically acceptable oral deliveryform, for use in the manufacture of a medicament in any indications asdefined under 1.1 to 1.6 above; or2.8. A pharmaceutical composition for use in any indications as definedunder 1.1 to 1.6 above comprising a calcitonin, e.g. salmon, (Asu1-7)-eel or human calcitonin in free form or salt form, in apharmaceutically acceptable oral delivery form, together with one ormore pharmaceutically acceptable diluents or carriers therefore.2.9. A pharmaceutical combination comprising:a) a first agent which is a calcitonin, e.g. salmon, (Asu 1-7)-eel orhuman calcitonin in free form or salt form, in pharmaceuticallyacceptable oral delivery form, andb) a co-agent which is selected from the group consisting of salmon,(Asu 1-7)-eel or human calcitonin, a calcitonin analogue or derivativethereof, COX-2 inhibitors, e.g. lumiracoxib (Prexige®), celecoxib(Celebrex®), rofecoxib (Vioxx®), valdecoxib (Bextra®), etoricoxib(Arcoxia®), or mixed COX-1 and COX-2 inhibitors, e.g. diclofenac,Etanercept (Enbrer), pain killers (e.g. Aspirin, Paracetamol), boneformers and bone antiresorbers. e.g. as disclosed above.3. A kit of parts for use in the prevention and/or treatment ofrheumatoid arthritis, said kit comprising:a) a first agent which is a calcitonin, e.g. salmon, (Asu 1-7)-eel orhuman calcitonin in free form or salt form, in pharmaceuticallyacceptable oral delivery form, andb) a co-agent which is selected from the group consisting of salmon,(Asu 1-7)-eel or human calcitonin, a calcitonin analogue or derivativethereof, COX-2 inhibitors, e.g. lumiracoxib (Prexige®), celecoxib(Celebrex®), rofecoxib (Vioxx®), valdecoxib (Bextra®), etoricoxib(Arcoxia®), or mixed COX-1 and COX-2 inhibitors, e.g. diclofenac,Etanercept (Enbrel®), pain killers (e.g. Aspirin, Paracetamol, boneformers and bone antiresorbers.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the dissolution profiles of tablets made with differentcompression forces (KN) and having different hardness values (Kp).

FIG. 2 graphically depicts serum c-terminal telopeptide of type IIcollagen (serum CTX-II) in % of control on day 21 after collageninjection for the groups control, collagen induced arthritis (CIA) andCIA+calcitonin.

FIG. 3 is a flow chart showing steps in preparing a formulation of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

In particular, the present invention relates to a method of preventingor treating Rheumatoid arthritis or a condition associated therewithsuch as inflammation of the joints, swelling of skeletal joints,cartilage and bone erosion and destruction, in a patient in need thereofcomprising administering orally to said patient a therapeuticallyeffective amount of a calcitonin, particularly a salmon calcitonin, an(Asu 1-7)-eel or human calcitonin, but more particularly a salmoncalcitonin, in free or salt form and a delivery agent for calcitonin. Inone embodiment of the invention, a method is provided for decreasingpain, associated with rheumatoid arthritis in a patient in need thereofcomprising administering orally to said patient a therapeuticallyeffective amount of a calcitonin in free or salt form and a deliveryagent for calcitonin.

In another embodiment, the invention relates to a method of preventingor treating Rheumatoid arthritis or a condition associated therewith ina patient in need thereof comprising administering orally to saidpatient a therapeutically effective amount of a calcitonin, particularlya salmon calcitonin, in free or salt form and a delivery agent forcalcitonin wherein the delivery agent is a compound of the followingformula I

-   -   wherein    -   R¹, R², R³, and R⁴ are independently hydrogen, —OH, —NR⁶R⁷,        halogen, C₁-C₄alkyl, or C₁-C₄alkoxy;    -   R⁵ is a substituted or unsubstituted C₂-C₁₆alkylene, substituted        or unsubstituted C₂-C₁₆alkenylene, substituted or unsubstituted        C₁-C₁₂alkyl(arylene), or substituted or unsubstituted        aryl(C₁-C₁₂alkylene); and    -   R⁶ and R⁷ are independently hydrogen, oxygen, or C₁-C₄ alkyl;        and a disodium salt, hydrates and alcohol solvates thereof.

In particular, the delivery agent is selected from the group of 5-CNAC,SNAD and SNAC, and their pharmaceutically acceptable salts; butparticularly a disodium salt of 5-CNAC, a disodium salt of SNAD, and adisodium salt of SNAC.

In another embodiment, the delivery agent used in the method accordingto the invention is provided in a micronized form, particularly in amicronized form with an average particle size of less than 40, moreparticularly of less than 20, and even more particularly of less than 10micrometers.

In still another embodiment, a method is provided according to theinvention, wherein the therapeutically effective amount of a calcitoninis delivered orally in a composition comprising the calcitonin which isconjugated to a polymer molecule.

In a further embodiment, a method is provided according to theinvention, wherein the therapeutically effective amount of a calcitoninis delivered in a therapeutically effective unit dosage form comprisingcalcitonin, at least one pharmaceutically acceptable pH-lowering agent,at least one absorption enhancer, and an enteric coating.

In particular, the invention relates to a method of preventing ortreating Rheumatoid arthritis or a condition associated therewith in apatient in need thereof comprising administering orally to said patienta therapeutically effective amount of a calcitonin, particularly asalmon calcitonin, in free or salt form and a delivery agent forcalcitonin wherein the therapeutically effective amount of calcitonin isin a dosage range of between 0.4 mg and 2.5 mg for a patient, e.g.human, e.g. an average human of about 70 kg together with a deliveryagent for calcitonin. More particularly, doses of around 0.8 mg, e.g.between 0.6 and 1.2 mg may be used in a method according to theinvention, even more particularly doses of less than 1 mg but higherthan 0.4 mg such as, for example, a dose of about 0.6-0.8 mg, e.g. 0.8mg, but especially a dose of about 0.8 mg, e.g. between 0.8 and 1.2 mg.Said doses are administered in a single or multiple dosage form, butparticularly once per day or, in the alternative, twice a day.

In still a further embodiment, the invention relates to the use of acalcitonin for the manufacture of a medicament for oral administrationcomprising a therapeutically effective amount of a calcitonin,particularly a salmon calcitonin, an (Asu 1-7)-eel or human calcitonin,but more particularly a salmon calcitonin, in free or salt form and adelivery agent for calcitonin for the prevention or treatment ofRheumatoid arthritis in a patient in need thereof, particularly adelivery agent which is a compound of the following formula I

-   -   wherein    -   R¹, R², R³, and R⁴ are independently hydrogen, —OH, —NR⁶R⁷,        halogen, C₁-C₄alkyl, or C₁-C₄alkoxy;    -   R⁵ is a substituted or unsubstituted C₂-C₁₆alkylene, substituted        or unsubstituted C₂-C₁₆alkenylene, substituted or unsubstituted        C₁-C₁₂alkyl(arylene), or substituted or unsubstituted        aryl(C₁-C₁₂alkylene); and    -   R⁶ and R⁷ are independently hydrogen, oxygen, or C₁-C₄ alkyl;        and a disodium salt, hydrates and alcohol solvates thereof.

In particular, the delivery agent is selected from the group of 5-CNAC,SNAD and SNAC, and their pharmaceutically acceptable salts; butparticularly a disodium salt of 5-CNAC, a disodium salt of SNAD, and adisodium salt of SNAC.

In another embodiment of the invention, the delivery agent according tothe invention is provided in a micronized form, particularly with anaverage particle size of less than 40, more particularly of less than20, and even more particularly of less than 10 micrometers.

In another embodiment of the invention, the calcitonin is used inconjugation with a polymer molecule.

In still another embodiment, the calcitonin is used together with atleast one pharmaceutically acceptable pH-lowering agent, at least oneabsorption enhancer, and an enteric coating. In particular, thecalcitonin is used in a therapeutically effective amount in free or saltform in a dosage range of between 0.4 mg and 2.5 mg for a patient, e.g.human, e.g. an average human of about 70 kg together with a deliveryagent for calcitonin. More particularly, doses of around 0.8 mg, e.g.between 0.6 and 1.2 mg may be used in a method according to theinvention, even more particularly doses of less than 1 mg but higherthan 0.4 mg such as, for example, a dose of about 0.6-0.8 mg, e.g. 0.8mg, but especially a dose of about 0.8 mg, e.g. between 0.8 and 1.2 mg.Said doses are administered in a single or multiple dosage form, butparticularly once per day or, in the alternative, twice a day.

In still another embodiment of the invention, a pharmaceuticalcomposition for use in the oral treatment or prevention of Rheumatoidarthritis, or of a condition associated therewith, in a patient in needthereof is provided, comprising a calcitonin, particularly a salmoncalcitonin, an (Asu 1-7)-eel or human calcitonin, but more particularlya salmon calcitonin, in free or salt form and a delivery agent forcalcitonin together with one or more pharmaceutically acceptablediluents or carriers therefore.

In particular, the invention relates to a pharmaceutical compositionaccording to the invention and as disclosed herein before, wherein thedelivery agent is a compound of the following formula I

-   -   wherein    -   R¹, R², R³, and R⁴ are independently hydrogen, —OH, —NR⁶R⁷,        halogen, C₁-C₄alkyl, or C₁-C₄alkoxy;    -   R⁵ is a substituted or unsubstituted C₂-C₁₆alkylene, substituted        or unsubstituted C₂-C₁₆alkenylene, substituted or unsubstituted        C₁-C₁₂alkyl(arylene), or substituted or unsubstituted        aryl(C₁-C₁₂alkylene); and    -   R⁶ and R⁷ are independently hydrogen, oxygen, or C₁-C₄ alkyl;        and a disodium salt, hydrates and alcohol solvates thereof.

More particularly, the invention relates to a pharmaceutical compositionaccording to the invention and as disclosed herein before, wherein thedelivery agent is selected from the group of 5-CNAC, SNAD and SNAC, andtheir pharmaceutically acceptable salts; but particularly a disodiumsalt of 5-CNAC, a disodium salt of SNAD, and a disodium salt of SNAC.

In another embodiment, the delivery agent used in the method accordingto the invention is provided in a micronized form, particularly in amicronized form with an average particle size of less than 40, moreparticularly of less than 20, and even more particularly of less than 10micrometers.

In still another embodiment the invention relates to a pharmaceuticalcomposition for oral delivery according to the invention comprisingcalcitonin in a therapeutically effective amount which is conjugated toa polymer molecule.

In still another embodiment the invention relates to a pharmaceuticalcomposition according to the invention, comprising a therapeuticallyeffective amount of a calcitonin and at least one pharmaceuticallyacceptable pH-lowering agent, at least one absorption enhancer, and anenteric coating.

In another embodiment of the invention, a pharmaceutical composition isprovided for preventing or treating Rheumatoid arthritis, or a conditionassociated therewith, in a patient in need thereof comprising atherapeutically effective amount of a calcitonin in free or salt form ina dosage range of between 0.4 mg and 2.5 mg together with a deliveryagent for calcitonin. More particularly, the pharmaceutical compositioncomprises calcitonin in a dosis range of around 0.8 mg, e.g. between 0.6and 1.2 mg, even more particularly of less than 1 mg but higher than 0.4mg such as, for example, a dosis range of about 0.6-0.8 mg, e.g. 0.8 mg,but especially a dosis range of about 0.8 mg, e.g. between 0.8 and 1.2mg. Said doses are administered in a single or multiple dosage form, butparticularly once per day or, in the alternative, twice a day.

In still another embodiment, the invention provides a pharmaceuticalcombination for use in the oral treatment or prevention of Rheumatoidarthritis in a patient in need thereof, comprising:

-   -   a. a first agent which is a calcitonin, particularly a salmon        calcitonin, an (Asu 1-7)-eel or human calcitonin, more        particularly a salmon calcitonin, which calcitonin is present in        a dosis range of between 0.4 and 2.5 mg, and    -   b. a co-agent which is selected from the group consisting of        salmon, (Asu 1-7)-eel or human calcitonin; a calcitonin analogue        or derivative thereof; COX-2 inhibitors, e.g. lumiracoxib        (Prexige®), celecoxib (Celebrex®), rofecoxib (Vioxx®),        valdecoxib (Bextra®), etoricoxib (Arcoxia®); or mixed COX-1 and        COX-2 inhibitors, e.g. diclofenac; Etanercept (Enbrel™); pain        killers (e.g. Aspirin, Paracetamol); bone Formers and bone        antiresorbers.

The term “oral” as used herein comprises any kind of oral deliveryroutes (comprising buccal and sublingual routes).

“Delivery agent” as used herein refers to carrier compounds or carriermolecules that are useful in the oral delivery of therapeutic agents.“Delivery agent” may be used herein interchangeably with “carrier”.

By a “Therapeutically effective amount” of calcitonin as provided in theoral dosage forms according to the present invention is to be understoodas an amount of calcitonin which is sufficient to achieve a clinicallysignificant improvement of a condition associated with Rheumatoidarthritis in a human or animal patient such as, for example, inhibitionof inflammation of the joints or the of the swelling of skeletal joints,inhibition, halting and/or reversion of cartilage and bone erosion anddestruction, and/or decrease of pain or which is sufficient to preventthe onset of said conditions.

The term “patient” as used herein means a patient in need of beingtreated or prevented from rheumatoid arthritis or any method as definedunder 1.1 to 2.3 above, whereas patient means mammals, such as rodents,cows, pigs, dogs, cats, and primates, particularly humans.

The term “pharmaceutical combination” as used herein means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients.

The term “fixed combination” means that the active ingredients, e.g.salmon calcitonin and a co-agent, are both administered to a patientsimultaneously in the form of a single entity or dosage.

The term “non-fixed combination” means that the active ingredients, e.g.salmon calcitonin and a co-agent, are both administered to a patient asseparate entities either simultaneously, concurrently or sequentiallywith no specific time limits, wherein such administration providestherapeutically effective levels of the 2 compounds in the body of thepatient.

“Oral Unit-Dose Form” refers to physically discrete units suitable forhuman and animal consumption and packaged individually as is known inthe art. It is contemplated for purposes of the present invention thatdosage forms of the present invention comprising therapeuticallyeffective amounts of calcitonin and a delivery agent may include one ormore unit doses (e.g., tablets, capsules) to achieve the therapeuticeffect.

The term “multiple dose” means that pharmaceutical composition accordingto the invention comprising therapeutically effective amounts ofcalcitonin and a delivery agent, particularly in form of a oral unitdose will be administered to a human or animal patient in at least twodoses in accordance with the dosing interval appropriate for thatcomposition.

The term “single dose” means that the pharmaceutical compositionaccording to the invention comprising therapeutically effective amountsof calcitonin and a delivery agent, particularly in form of a oral unitdose will be administered to a human or animal patient in a single dose.

Preferably the calcitonin, e.g. salmon calcitonin in free form or inpharmaceutically acceptable salt form, is co-administered with aprotease inhibitor, e.g. cathepsin inhibitor, e.g. cathepsin Kinhibitor.

Utility of calcitonin, e.g. salmon calcitonin in free form or salt form,in pharmaceutically acceptable oral delivery form for use in any methodas defined under 1.1 to 1.10 or in any pharmaceutical composition asdisclosed herein before, may be demonstrated in animal test methods aswell as in clinic.

In an embodiment of the invention, a pharmaceutical composition for usein the oral treatment or prevention of Rheumatoid arthritis, or of acondition associated therewith, in a patient in need thereof isprovided, comprising a calcitonin, particularly a salmon calcitonin, infree or salt form and a delivery agent for calcitonin, and, optionally,a conventional pharmaceutically acceptable excipient.

The calcitonin can be any calcitonin, including natural, synthetic orrecombinant sources thereof, as well as calcitonin derivatives such as1,7-Asu-eel calcitonin. The compositions can comprise a singlecalcitonin or any combination of two or more calcitonins. The preferredcalcitonin is synthetic salmon calcitonin.

Various calcitonins, including salmon, pig and eel calcitonin arecommercially available or may be synthesized by known methods.

Dosage forms for oral administration include tablets, capsules,lozenges, pills, wafers, granules, oral liquids such as syrups,suspensions, solutions, emulsions, powder for reconstitution.

For the purpose of the present invention, a therapeutically effectivedosage will generally be from about 0.4 mg/day to about 2.5 mg/day,particularly from about 0.6 mg/day to about 1.2 mg/day, and moreparticularly from about 0.6 mg/day to about 0.8 mg/day or form about 0.8mg/day to about 1.2 mg/day, which may be administered in one or multipledoses, particularly once or twice a day to a patient, e.g. a human, e.g.an average human of about 70 kg.

When the pharmacologically active agent is salmon calcitonin, theappropriate dosage will, of course, vary depending upon, for example,the host and the nature and severity of the condition being treated. Inparticular, the specific dose level of the compounds of the inventionfor any particular patient will depend on a variety of factors such asage, sex, body weight, general health condition, diet, individualresponse of the patient to be treated time of administration, severityof the disease to be treated, the activity of particular compoundapplied, dosage form, mode of application and concomitant medication.The therapeutically effective amount for a given situation will readilybe determined by routine experimentation and is within the skills andjudgment of the ordinary clinician or physician.

However, in general, satisfactory results will be obtained systemicallyat daily dosages of from about 0.5 μg/kg to about 10 μg/kg animal bodyweight, preferably 1 μg/kg to about 6 μg/kg body weight. For an averagehuman of about 70 kg this translates into a daily dosage of from about0.035 to 0.7 mg, particularly from about 0.07 mg to about 0.42 mg.

In another embodiment of the invention, a therapeutically effectivedosage of calcitonin will generally be from about 0.035 mg/day to 0.7mg/day, particularly from about 0.07 mg/day to about 0.42 mg/day; butespecially from about 0.42 mg/day to about 0.7 mg/day.

The pharmaceutically acceptable inactive excipients which are used inthe oral formulation of calcitonin, may include polymers and inactivecompounds which for example, aid the formulation or manufacturing of thesolid oral dosage form contemplated by the present invention or whichmay aid the release of the solid oral composition in thegastro-intestinal environment. The pharmaceutically inactiveingredients, referred to above, for example optionally includecrospovidones and povidones, which may be any crospovidone and povidone.Crospovidone is a synthetic crosslinked homopolymer ofN-vinyl-2-pyrrolidone, also called 1-ethenyl-2-pyrrolidinone, having amolecular weight of 1,000,000 or more. Commercially availablecrospovidones include Polyplasdone XL, Polyplasdone XL-10, PolyplasdoneINF-10 available from ISP, Kollidon CL, available from BASF Corporation.The preferred crospovidone is Polyplasdone XL. Povidone is a syntheticpolymer consisting of linear 1-vinyl-2-pyrrolidinone groups having amolecular weight generally between 2,500 and 3,000,000. Commerciallyavailable povidones include Kollidon K-30, Kollidon K-90F available fromBASF Corporation and Plasdone K-30 and Plasdone K-29/32, available fromISP. As mentioned above, the crospovidones and povidones arecommercially available. Alternatively, they may be synthesized by knownprocesses. The crospovidone, povidone or combination thereof isgenerally present in the compositions in an amount of from 0.02 to 50percent by weight, particularly in an amount of from 0.5 to 50 percentby weight relative to the total weight of the overall pharmaceuticalcomposition, preferably an amount of from 2 to 25 percent, morepreferably 5 to 20 percent by weight, but especially of from 3 to 7percent by weight relative to the total weight of the pharmaceuticalcomposition.

The delivery agents useful in the formulation, e.g. the oralformulation, are any agents useful for delivering the particularpharmacologically active agent. Suitable delivery agents are any one ofthe modified amino acids disclosed in aforementioned U.S. Pat. No.5,866,536 or any one of the modified amino acids described in theaforementioned U.S. Pat. No. 5,773,647 or any combination thereof. Thecontents of the aforementioned U.S. Pat. Nos. 5,773,647 and 5,866,536are hereby incorporated by reference in their entirety. In addition, thedelivery agent can be the disodium salt of any of the aforementionedmodified amino acids as well as ethanol solvates and hydrates thereof.Suitable compounds include compounds of the following formula I

wherein

-   -   R¹, R², R³, and R⁴ are independently hydrogen, —OH, —NR⁶R⁷,        halogen, C₁-C₄alkyl, or C₁-C₄alkoxy;    -   R⁵ is a substituted or unsubstituted C₂-C₁₆alkylene, substituted        or unsubstituted C₂-C₁₆alkenylene, substituted or unsubstituted        C₁-C₁₂alkyl(arylene), or substituted or unsubstituted        aryl(C₁-C₁₂alkylene); and    -   R⁶ and R⁷ are independently hydrogen, oxygen, or C₁-C₄ alkyl;        and hydrates and alcohol solvates thereof. The compounds of        formula I as well as their disodium salts and alcohol solvates        and hydrates thereof are described in WO 00/059863, along with        methods for preparing them.

The disodium salt may be prepared from the ethanol solvate byevaporating or drying the ethanol solvate by methods known in the art toform the anhydrous disodium salt. Drying is generally carried out at atemperature of from about 80 to about 120° C., preferably from about 85to about 90° C., and most preferably at about 85° C. The drying step isgenerally performed at a pressure of 26″ Hg or greater. The anhydrousdisodium salt generally contains less than about 5% by weight of ethanoland preferably less than about 2% by weight of ethanol, based on 100%total weight of anhydrous disodium salt. The disodium salt of thedelivery agent can also be prepared by making a slurry of the deliveryagent in water and adding two molar equivalents of aqueous sodiumhydroxide, sodium alkoxide or the like. Suitable sodium alkoxidesinclude, but are not limited to, sodium methoxide, sodium ethoxide, andcombinations thereof. A still further method of preparing the disodiumsalt is by reacting the delivery agent with one molar equivalent ofsodium hydroxide to yield the disodium salt. The disodium salt can beisolated as a solid by concentrating the solution containing thedisodium salt to a thick paste by vacuum distillation. This paste may bedried in a vacuum oven to obtain the disodium salt of the delivery agentas a solid. The solid can also be isolated by spray drying an aqueoussolution of the disodium salt. The delivery agents may be prepared bymethods known in the art, e.g., as mentioned above, by methods describedin U.S. Pat. Nos. 5,773,647 and 5,866,536. The ethanol solvates, asdescribed in the aforementioned WO 00/059863, include, but are notlimited to, a molecular or ionic complex of molecules or ions of ethanolsolvent with molecules or ions of the disodium salt of the deliveryagent. Typically, the ethanol solvate contains about one ethanolmolecule or ion for every molecule of disodium salt of the deliveryagent. The ethanol solvate of the disodium salt of the delivery agentcan be prepared by dissolving the delivery agent in ethanol. Typically,each gram of delivery agent is dissolved in from about 1 to about 50 mLof ethanol and generally, from about 2 to about 10 mL of ethanol. Thedelivery agent/ethanol solution is then reacted with a molar excess of asodium containing salt, such as a monosodium containing salt, relativeto delivery agent, i.e. for every mole of delivery agent there is morethan one mole of sodium cations, yielding the ethanol solvate. Suitablemonosodium salts include, but are not limited to, sodium hydroxide;sodium alkoxides, such as sodium methoxide and sodium ethoxide; and anycombination of the foregoing. Preferably, at least about two molarequivalents of the monosodium containing salt are added to the ethanolsolution, i.e. for every mole of delivery agent there is at least abouttwo moles of sodium cations. Generally, the reaction is performed at orbelow the reflux temperature of the mixture, such as at ambienttemperature. The ethanol solvate is then recovered by methods known isthe art, such as, concentration of the resulting slurry at atmosphericdistillation, cooling the concentrated slurry and filtering the solid.The recovered solid can then be vacuum dried to obtain the ethanolsolvate. The hydrates of the disodium salts of the delivery agents maybe prepared by drying the ethanol solvate to from an anhydrous disodiumsalt, as described above, and hydrating the anhydrous disodium salt.Preferably, the monohydrate of the disodium salt is formed. Since theanhydrous disodium salt is very hydroscopic, the hydrate forms uponexposure to atmospheric moisture. Generally, the hydrating step isperformed at from about ambient temperature to about 50° C., preferablyambient temperature to about 30° C. and in an environment having atleast 50% relative humidity. Alternatively, the anhydrous disodium saltmay be hydrated with steam.

The preferred delivery agents are N-(5-chlorosalicyloyl)-8-aminocaprylicacid (5-CNAC), N-(10-[2-hydroxybenzoyl]amino)decanoic acid (SNAD),N-(8-[2-hydroxybenzoyl]amino)caprylic acid (SNAC) and theirpharmaceutically acceptable salts, preferably their monosodium anddisodium salts, ethanol solvates of their sodium salts and themonohydrates of their sodium salts and any combinations thereof.

The most preferred delivery agent is the disodium salt of 5-CNAC and themonohydrate thereof. Preferably the disodium salt is present in amountof more than 90% weight per total weight of the 5-CNAC present in thecomposition.

The active ingredient to delivery agent ratio is particularly presentbetween 1/25 to 1/600, more particularly between 1/25 to 1/400, evenmore particularly between 1/200 and 1/300 and 1/400 and 1/600,respectively, with the most preferred ratio in the case sCT/5-CNACcompositions being of 0.5 mg-1 mg sCT to 200 mg-300 mg of 5-CNACdisodium salt.

The delivery agent, 5 CNAC, SNAD, and SNAG are very water soluble andnearly fully, i.e. greater than 90%, absorbed by the gastro-intestinaltract whether it is ingested in micronized or coarse form. However, ithas been found, surprisingly, that when a micronized form of one ofthese carrier agents is employed in the composition, the absorption ofthe pharmacologically active agent of the present composition is morecompletely absorbed into the blood stream. A micronized form of thecarrier agent, which is utilized in preparation of the solid oral dosageform of the present invention, is defined as a carrier agent which, whenadded to the present composition mixture of pharmacologically activeagent and pharmaceutically inactive ingredients, has an average particlesize of less than 40 micrometers. Desirably the carrier agent of thepresent invention has a micronized form which is defined as an averageparticle size of less than 20 microns. More interestingly, the carrieragent for the present invention has a micronized form which is definedas an average particle size of less than 10 microns. Micronized forms ofthe carrier agent of the present invention may be prepared by grindingit in a grinding mill which is acceptable for grinding pharmaceuticalingredients and which is capable of grinding the pharmaceuticalingredients and/or carrier agent to a fine and uniform micronizedparticle size. An example of such a grinding mill is an Air Jet Mill GemT® (Copley Scientific, Ltd., Nottingham, UK). The finely ground carrieragent either separately or finely ground carrier agent plus anycombination of finely ground additional ingredients of the presentinvention may then be screened, for example, over a mesh screen havingthe appropriate openings, in order to allow only those ingredients whichhave the required particle size to pass through and be collected for usein the present invention. The pharmaceutical compositions of the presentinvention typically contain a delivery effective amount of one or moreof the delivery agents, i.e. an amount sufficient to deliver the activeagent for the desired effect. Generally, the delivery agent is presentin an amount of 2.5% to 99.4% by weight, more preferably 25% to 50% byweight.

Preferably a calcitonin, e.g. salmon calcitonin in free form or in saltform, is delivered as an oral pharmaceutical composition comprisingcalcitonin and a delivery agent for calcitonin. More preferably saidoral pharmaceutical composition comprises a delivery agent selected fromthe group of 5-CNAC, SNAD, and SNAC. More preferably said oralpharmaceutical composition comprises a delivery agent is selected fromthe group consisting of a disodium salt of 5-CNAC, a disodium salt ofSNAD, and a disodium salt of SNAC. More preferably, said oralpharmaceutical composition comprises a delivery agent in micronizedform.

The pharmaceutically acceptable oral delivery form of the compositionaccording to the invention may further comprise a diluent.

The diluent may be, for example Avicel PH 102 or 101. The diluent may bepresent in the pharmaceutical composition of up to 90 wt % based on thewhole composition, or may be used to make up any difference between thedesired and actual final pharmaceutical composition mass, which may be,for example up to 600 mg, e.g. 500 mg. Preferably, the binder is presentin an amount of between 20 and 70 wt % based on the whole composition,e.g. 40 to 60 wt %, e.g. 50 wt %. Where the final pharmaceuticalcomposition weight is 500 mg, this equates to amounts of, for example,100 mg to 350 mg.

In a preferred embodiment of the present invention, the diluent is amicrocrystalline cellulose.

Alternatively, calcitonin can be orally delivered also with othertechnologies such as the one described in WO 94/26778; U.S. Pat. No.5,359,030; U.S. Pat. No. 5,438,040; U.S. Pat. No. 5,681,811; U.S. Pat.No. 6,191,105; U.S. Pat. No. 6,309,633; U.S. Pat. No. 6,380,405; U.S.Pat. No. 6,436,990; U.S. Pat. No. 6,458,776; and U.S. Pat. No. 6,479,692(the content thereof is hereby incorporated by reference in itsentirety). In short, such oral formulations relate generally toconjugation-stabilized (poly)peptide and protein compositions.

More particularly, such oral delivery forms relate in one broadcompositional aspect to covalently conjugated calcitonin complexeswherein the calcitonin is covalently bonded to one or more molecules ofa polymer incorporating as an integral part thereof a hydrophilicmoiety, e.g., a linear polyalkylene glycol, and wherein said polymerincorporates a lipophilic moiety as an integral part thereof. In oneparticular aspect, such oral delivery forms relate to a physiologicallyactive calcitonin composition comprising a physiologically activepeptide covalently coupled with a polymer comprising (i) a linearpolyalkylene glycol moiety and (ii) a lipophilic moiety, wherein thepeptide, linear polyalkylene glycol moiety, and the lipophilic moietyare conformationally arranged in relation to one another such that thephysiologically active peptide in the physiologically active calcitonincomposition has an enhanced in vivo resistance to enzymatic degradation,relative to the physiologically active calcitonin alone (i.e., in anunconjugated form devoid of the polymer coupled thereto). In anotheraspect, such oral delivery forms relate to a physiologically activecalcitonin composition of three-dimensional conformation comprising aphysiologically active calcitonin covalently coupled with a polysorbatecomplex comprising (i) a linear polyalkylene glycol moiety and (ii) alipophilic moiety, wherein the physiologically active calcitonin, thelinear polyalkylene glycol moiety and the lipophilic moiety areconformationally arranged in relation to one another such that (a) thelipophilic moiety is exteriorly available in the three-dimensionalconformation, and (b) the physiologically active calcitonin in thephysiologically active calcitonin composition has an enhanced in vivoresistance to enzymatic degradation, relative to the physiologicallyactive calcitonin alone. In a further aspect, such oral delivery formsrelate to a multiligand conjugated calcitonin complex comprising atriglyceride backbone moiety, having: a bioactive calcitonin covalentlycoupled with the triglyceride backbone moiety through a polyalkyleneglycol spacer group bonded at a carbon atom of the triglyceride backbonemoiety; and at least one fatty acid moiety covalently attached eitherdirectly to a carbon atom of the triglyceride backbone moiety orcovalently joined through a polyalkylene glycol spacer moiety. In suchmulti ligand conjugated calcitonin complex, the d and B carbon atoms ofthe triglyceride bioactive moiety may have fatty acid moieties attachedby covalently bonding either directly thereto, or indirectly covalentlybonded thereto through polyalkylene glycol spacer moieties.Alternatively, a fatty acid moiety may be covalently attached eitherdirectly or through a polyalkylene glycol spacer moiety to the a and dcarbons of the triglyceride backbone moiety, with the bioactivecalcitonin being covalently coupled with the 13-carbon of thetriglyceride backbone moiety, either being directly covalently bondedthereto or indirectly bonded thereto through a polyalkylene spacermoiety. In such a multiligand conjugated calcitonin complex, thebioactive calcitonin may advantageously be covalently coupled with thetriglyceride modified backbone moiety through alkyl spacer groups, oralternatively other acceptable spacer groups, within the broad scope ofthe invention. As used in such context, acceptability of the spacergroup refers to steric, compositional, and end use application specificacceptability characteristics. In yet another aspect such oral deliveryforms relate to a polysorbate complex comprising a polysorbate moietyincluding a triglyceride backbone and functionalizing groups including:(i) a fatty acid group; and (ii) a polyethylene glycol group having aphysiologically active moiety covalently bonded thereto, e.g., aphysiologically active moiety is covalently bonded to an appropriatefunctionality of the polyethylene glycol group.

Such covalent bonding may be either direct, e.g., to a hydroxy terminalfunctionality of the polyethylene glycol group, or alternatively, thecovalent bonding may be indirect, e.g., by reactively capping thehydroxy terminus of the polyethylene glycol group with a terminalcarboxy functionality spacer group, so that the resulting cappedpolyethylene glycol group has a terminal carboxy functionality to whichthe physiologically active moiety may be covalently bonded. Such oraldelivery forms relate to a further aspect to a stable, aqueouslysoluble, conjugated calcitonin complex comprising a physiologicallyactive calcitonin covalently coupled to a physiologically compatiblepolyethylene glycol modified glycolipid moiety. In such complex, thephysiologically active calcitonin may be covalently coupled to thephysiologically compatible polyethylene glycol modified glycolipidmoiety by a labile covalent bond at a tee amino acid group of thepolypeptide. The physiologically compatible polyethylene glycol modifiedglycolipid moiety may advantageously comprise a polysorbate polymer,e.g., a polysorbate polymer comprising fatty acid ester groups selectedfrom the group consisting of monopalmitate, dipalmitate, monolaurate,dilaurate, trilaurate, monoleate, dioleate, trioleate, monostearate,distearate, and tristearate. In such complex, the physiologicallycompatible polyethylene glycol modified glycolipid moiety may suitablycomprise a polymer selected from the group consisting of polyethyleneglycol ethers of fatty acids, and polyethylene glycol esters of fattyacids, wherein the fatty acids for example comprise a fatty acidselected from the group consisting of lauric, palmitic, oleic, andstearic acids. In the above complex, the physiologically activecalcitonin may by way of illustration comprise a calcitonin selectedfrom the group consisting of insulin, calcitonin, ACTH, glucagon,somatostatin, somatotropin, somatomedin, parathyroid hormone,erythropoietin, hypothalmic releasing factors, prolactin, thyroidstimulating hormones, endorphins, enkephalins, vasopressin,non-naturally occurring opiods, superoxide dismutase, interferon,asparaginase, arginase, arginine deaminease, adenosine deaminaseribonuclease, trypsin, chemotrypsin, and papain. In another aspect, thepresent invention relates to an oral administration dosage form for themediation of insulin deficiency, comprising a pharmaceuticallyacceptable carrier and a stable, aqueously soluble, conjugated insulincomplex comprising insulin or proinsulin covalently coupled to aphysiologically compatible polyethylene glycol modified glycolipidmoiety.

Furthermore, a further second alternative oral delivery dosage formwhich may be used according to the invention is a technology describedin WO 97/33531; U.S. Pat. No. 5,912,014 and US 608618 (the contentthereof is hereby incorporated by reference in its entirety). In short,such further oral delivery form protects calcitonin from the acidicenvironment and digestive enzymes as it passes through the stomach andintestine, and facilitates its entry into the bloodstream. Once it issafely in the bloodstream, calcitonin can exert its therapeutic effect.Such oral delivery form is e.g. a pharmaceutical composition for oraldelivery of salmon calcitonin comprising: (A) a therapeuticallyeffective amount of said salmon calcitonin; (B) at least onepharmaceutically acceptable pH-lowering agent; (C) at least oneabsorption enhancer effective to promote bioavailability of said salmoncalcitonin; and (D) an enteric coating; wherein said pH-lowering agentis present in said pharmaceutical composition in a quantity which, ifadded to 10 milliliters of 0.1 M aqueous sodium bicarbonate solutionswould be sufficient to lower the pH of said solution to no higher than5.5. The pharmaceutical composition, wherein said enteric coating ispresent at a weight which is no more than 20% of the weight of theremainder of said pharmaceutical composition excluding said entericcoating. The pharmaceutical composition of above, wherein said entericcoating is present at a weight which is no more than 5-15% of the weightof the remainder of said pharmaceutical composition excluding saidenteric coating.

The oral pharmaceutical compositions with which the usefulness ofcalcitonin in the treatment of rheumatoid arthritis is shown, may beprovided as a capsule including a soft-gel capsule, tablet, caplet,other solid oral dosage form, all of which can be prepared by methodswell known in the art.

The solid pharmaceutical compositions of the instant invention can beprepared by first grinding either the carrier agent or the carrier agentwith any combination of the additional ingredients of the presentcomposition to a micronized particle size. The micronized carrier agentor micronized carrier agent plus micronized additional ingredients ofthe present invention may then be further processed by conventionalmethods e.g. by blending a mixture of the active agent or active agents,the delivery agent, the crospovidone or povidone and other ingredients,kneading, and filling into capsules or, instead of filling intocapsules, molding followed by further tableting or compression-moldingto give tablets. In addition, a solid dispersion may be formed by knownmethods followed by further processing to form a tablet or capsule.

The following examples serve to further illustrate the invention andwill be readily understood by one of ordinary skill in the art. Theexamples are not meant to be limiting of the present invention in anyway.

EXAMPLES A. Formulation Examples Example 1 Formulation 1 (3 Batches)

Preparation of Micronized 5-CNAC: Coarse 5-CNAC, which is to bemicronized, is added to a jet mill (Air Jet Mill Gem T® CopleyScientific, Ltd., Nottingham, UK) using a 80 ceramic pan cake jet mill,8 cm diameter, 6 bar N2, 0.5 mm nozzles with manual feed of about 700g/h. The coarse 5-CNAC is jet milled and periodically sampled undermicroscope with reference ruler measurements to identify when theaverage desired micronized particle size is obtained. Three differentbatches are ground to create a mean particle size, i.e. D50=6 um, 35 um,and 46 um batches. Individual sieving of the separate micronized batchesis then done by using a conical sieve mill (Quadro Comil, QuadroEngineering Incorporated 613 Colby Drive, Waterloo, Ontario, Canada N2V1A1) with a U10, 813 um conical sieve, round beater, operating at 1500rpm with throughput of about 150 kg/h.

Formulation 1-3. Salmon Calcitonin Formulation with 5-CNAC of DifferentParticle Size

Ingredient Amount (mg) Percent (%) Salmon Calcitonin 1 0.25 Micronized5-CNAC 228 57 Avicel PH 102 ® 147 36.75 Crospovidone, NF 20 5 Magnesiumstearate 4 1 Total 400 100

Preparation of Formulation 1: Three different batches of tablets areprepared using the three different batches of micronized 5-CNACdisodium, one tablet batch having an average 5-CNAC disodium particlesize of 46 microns (Batch A), a second tablet batch having an average5-CNAC disodium particle size of 6 microns (Batch B), and a third tabletbatch having an average 5-CNAC disodium particle size of 35 microns(Batch C). 0.50 g of salmon calcitonin, pre-screened through a 40 meshscreen, 57. g of micronized 5-CNAC disodium salt, screened through a 35mesh screen, and 10 g of Polyplasdone XL (crospovidone, NF,International Specialty Products, 1361 Alps Road, Wayne, N.J., 07470,USA) is combined in a 500 mL jar and is mixed using a Turbula mixer for100 revolutions at a speed of 46 RPM. An additional 57. g of micronized5-CNAC disodium salt, screened through a 35 mesh screen, and 36.75 g ofAvicel PH 102® is added to the jar and mixed for 500 revolutions at aspeed of 46 RPM. A further 36.75 g of Avicel PH 102® is added to the jarand is mixed for an additional 100 revolutions at a speed of 46 RPM. 2.0g of magnesium stearate is screened into the jar using a 35 mesh screenand is blended for 1 minute at a speed of 46 RPM. The final blend iscompressed into tablets using a Manesty B3B tablet press. The tabletweight is approximately 400 mg.

Example 2 Preparation of Formulations 2-3

Alternatively, there are further formulations provided:

Formulation 2:

Ingredient % for batch Batch mg per tablet Recombinant 0.12 0.6 Salmoncalcitonin 5-CNAC (I) 0.24a 1.2 5-CNAC (II) 45.36b 226.8 Avicel PH 101(I) 3a 15a Avicel PH 101 (II) 44.9b 224.9b Crospovidone 5 25 Aerosil 200PH 0.3 1.5 Magnesium stearate 1.0 5 Total tablet weight (mg) 100 500Unit weight (a + b) listed as 5-CNAC disodium salt, corresponding tocombined weight of 200 mg 5-CNAC free acid. Unit weight (a + b) ofAvicel PH 101 (I) and (II) corresponds to combined weight of Avicel PH101.

Formulation 3

Ingredient % for batch Batch mg per tablet Recombinant 0.16 0.8 Salmoncalcitonin 5-CNAC (I) 2.1a 4.8a 5-CNAC (II) 2.1b 4.8b 5-CNAC (III) 41.4c218.4c Avicel PH 101 (I) 3a 15a Avicel PH 101 (II) 44.9b 224.7bCrospovidone 5 25 Aerosil 200 PH 0.3 1.5 Magnesium stearate 1.0 5 Totaltablet weight (mg) 100 500 Unit weight (a + b + c) listed as 5-CNACdisodium salt, corresponding to combined weight of 200 mg 5-CNAC freeacid. Unit weight (a + b) of Avicel PH 101 (I) and (II) corresponds tocombined weight of Avicel PH 101.

The process for preparation of the above formulations are similar tothat of the one, described in Example 1. However, there is somedeviation which are described below as well as depicted in FIG. 3:

-   1 Weight 0.25 g of sCT DS;-   2 Blend with Part I of 5-CNAC;-   3 Sieve blended material from Step 2 through #60 (0.25 mm) screen;-   4 Rinse the screen from Step 3 with Part II of 5-CNAC;-   5 Sieve Aerosil 200PH and Part I of Avicel PH101 through #20    (0.85 mm) mesh screen;-   6 Add Avicel PH101 (Part II), sieved material from Step 5,5-CNAC    (Part III), sieved material from Step 4, Crospovidone into diffusion    blender and blend for 150 revolutions;-   7 Sieve the blended material through #20 mesh (0.85 mm) screen;-   8 Sieve Mg Stearate through #20 mesh (0.85 mm) screen and add to    blend from Step 7;-   9 Lubrication for 50 revolutions-   10. Compress the blend into 12 mm round FFBE tablets with NVR/984    embossing. All the equipments used are the same as described in    Example 1.

Example 3 Preparation of Formulation 4

The above mentioned formulation 2 is compressed into tablets withvarious hardness using Manesty Beta press or Fette 3090 using differentcompression forces. Resultant tablets having different dissolutionprofiles were tested in Rhesus Monkeys for oral absorption of sCT.Tablets and their physical properties are listed in Table 1 and 2 below:

TABLE 1 0.6 mg Speed: 197600 tab/hr which is 27 rpm Force Weight WeightThickness Hardness Hardness (KN) (mg) RSD (mm) (Kp) range DT Friability5.5 500.58 0.58 4.95 5.88 5.7-6.1 30 s 6 504.15 0.89 4.86 6.79 5.7-7.740 s 0.73 7.1 503.68 1.01 4.6 9.41  8.3-10.4 2 m 30 s-2 m 15 s 0.25 8499.68 0.69 4.52 10.24  9.8-10.9 3 m 40 s-5 m 35 s 0.52 8.5 502.04 0.934.47 11.7 11.2-12.8 4 m 30 s-5 m 46 s 0.25 9 505.74 0.62 4.43 1211.7-12.6 6 m 15 s-7 m 55 s 0.14 10.2 504.8 0.57 4.31 13.74 12.8-14.6 7m 19 s-8 m 8 s

TABLE 2 0.8 mg Speed: 329400 tab/hr which is 45 rpm Force Weight WeightThickness Hardness Hardness (KN) (mg) RSD (mm) (Kp) range DT Friability5.1 497.01 0.67 4.88 2.94 2.4-3.1 20 s 1.1  (severe chipping) 6.4 497.970.75 4.66 4.22 3.7-4.7 30-35 s 0.38 (slight chipping) 7 499.49 1 4.55.26 4.6-6.0 1 m 10 s 0.44 8 496.66 0.57 4.43 6.51 6.0-7.1 2 m 42 s 0.149.1 497.56 0.55 4.31 7.87 7.5-8.3 2 m 35 s-3 m 59 s 0.1  10 503.16 0.714.25 8.34   8-8.9 3 m 40 s-4 m 30 s 0.05 11.2 503.21 0.66 4.18 9.65 9.3-10.1 5 m 40 s-6 m 55 s 0.03 12.1 502.76 0.39 4.05 11-5 10.9-11.8 8m 34 s

Where: RSD is Relative Standard Deviation; and

DT is disintegration timeand their dissolution profiles are outlined in FIG. 1.

Example 4 Induction and Assessment of Arthritis

Arthritis induced in rodents by the systemic administration of type IIcollagen (CII) is an experimental model with many resemblances to RA,and is widely used for studying the disease processes (reviewed inWooley P H, Chapedelaine J M. Immunogenetics of collagen-inducedarthritis. Crit. Rev Immunol 1987; 8: 1-22; and Trentham D E. Collagenarthritis as a relevant model for rheumatoid arthritis. Arth Rheum 1982;25: 911-6).

Upon immunization with purified CII in complete Freund's adjuvant,genetically susceptible strains of rodents develop arthritis, which ischaracterized by cellular and humoral immune responses to CII. Like RA,collagen-induced arthritis (CIA) is characterized by the rapid onset ofinflammation of joints followed by the erosion of cartilage and bone.

Highly purified bovine CIA type II collagen can be obtained fromChondrex, Inc., 2607 151st Place NE, Redmond, Wash. 98052, USA

Animals (Male Lewis rats or Male DBA/1 J mice (H-2^(q)) (HarlanLaboratories UK, Oxford, UK) are injected intradermally at the base oftheir tails with a single injection of 100 μg of CII, emulsified incomplete Freund's adjuvant (Difco, Detroit, Mich., USA) at 8-10 weeks ofage.

Animals are monitored for signs of arthritis one week post immunizationon a daily basis and a clinical scoring system is adopted wherein eachlimb is given a clinical score on the basis of visual signs of oedemaand/or erythema as follows: 0=normal, 1=slight swelling and/or erythemaat the base of the paw, 2=frank oedema and erythema involving the entirepaw, 2.5=pronounced oedema and erythema leading to an incapacitated limbmobility, 3=ankylosis, as previously described in Malfait A M, Butler DM, Presky D H et al. Blockade of IL-12 during the induction ofcollagen-induced arthritis (CIA) markedly attenuates the severity of thearthritis. Clin Exp Immunol 1998; 111: 377-83.

Each limb is graded in this way, giving a maximum possible score of 12per animal. The hind paws are also measured daily, for paw swelling withthe help of a calliper (least detectable change=0.1 mm, Kroeplin,Schluchtem, Germany).

In the present study, rheumatoid Arthritis was induced in the CollagenInduced Arthritis model (CIA-model) in lewis rats (8-9 weeks), byintradermal injection of porcine collagen type II.

In the non-treated collagen-injected group (CIA-group) disease occurredfrom day 11-14. In the treatment group rats were treated twice dailywith either 50 mg/kg 5-CNAC, 50 mg/kg 5-CNAC+calcitonin 2 mg/kg.

Results are shown in FIG. 2, where serum c-terminal telopeptide of typeII collagen (serum CTX-II) in % of control on day 21 after collageninjection is shown for the different groups (control, CIA andCIA+Calcitonin).

Disease was detected in the CIA-group by a significant increase in serumc-terminal telopeptide of type II collagen (serum CTX-II) compared tocontrol. Treatment with Calcitonin was able to reduce this by 33%.

1. A method of preventing or treating Rheumatoid arthritis in a patientin need thereof comprising administering orally to said patient atherapeutically effective amount of a calcitonin in free or salt formand a delivery agent for calcitonin.
 2. A method for inhibitinginflammation of the joints associated with rheumatoid arthritis in apatient in need thereof comprising administering orally to said patienta therapeutically effective amount of a calcitonin in free or salt formand a delivery agent for calcitonin.
 3. A method for inhibiting swellingof skeletal joints associated with rheumatoid arthritis in a patient inneed thereof comprising administering orally to said patient atherapeutically effective amount of a calcitonin in free or salt formand a delivery agent for calcitonin.
 4. A method for inhibiting, haltingor reversing the cartilage and bone erosion and destruction associatedwith rheumatoid arthritis in a patient in need thereof comprisingadministering orally to said patient a therapeutically effective amountof a calcitonin in free or salt form and a delivery agent forcalcitonin.
 5. A method for decreasing pain, associated with rheumatoidarthritis in a patient in need thereof comprising administering orallyto said patient a therapeutically effective amount of a calcitonin infree or salt form and a delivery agent for calcitonin.
 6. The methodaccording to claim 1, wherein said calcitonin is salmon calcitonin. 7.The method according to claim 1, wherein the delivery agent is acompound of the following formula I

wherein R¹, R², R³, and R⁴ are independently hydrogen, —OH, —NR⁶R⁷,halogen, C₁-C₄alkyl, or C₁-C₄alkoxy; R⁵ is a substituted orunsubstituted C₂-C₁₆alkylene, substituted or unsubstitutedC₂-C₁₆alkenylene, substituted or unsubstituted C₁-C₁₂alkyl(arylene), orsubstituted or unsubstituted aryl(C₁-C₁₂alkylene); and R⁶ and R⁷ areindependently hydrogen, oxygen, or C₁-C₄ alkyl; and hydrates and alcoholsolvates thereof.
 8. The method according to claim 7, wherein thedelivery agent is a disodium salt, an alcohol solvate or a hydrate of acompound of formula I.
 9. The method according to claim 1, wherein thedelivery agent is selected from the group of 5-CNAC, SNAD, and SNAC andtheir pharmaceutically acceptable salts.
 10. The method according toclaim 1, wherein said pharmaceutical composition comprises a deliveryagent selected from the group consisting of a disodium salt of 5-CNAC, adisodium salt of SNAD, and a disodium salt of SNAC.
 11. The methodaccording to claim 1, wherein said pharmaceutical composition comprisesa delivery agent in micronized form.
 12. The method according to claim11 wherein said micronized delivery agent has an average particle sizeof less than 40, particularly of less than 20, more particularly of lessthan 10 micrometers.
 13. The method according to claim 1, wherein thetherapeutically effective amount of a calcitonin is delivered orally ina composition comprising the calcitonin which is conjugated to a polymermolecule.
 14. The method according to claim 1, wherein thetherapeutically effective amount of a calcitonin is delivered with aneffective dosage of an oral pharmaceutical composition comprisingcalcitonin, at least one pharmaceutically acceptable pH-lowering agent,at least one absorption enhancer, and an enteric coating.
 15. The methodaccording to claim 1, for preventing or treating Rheumatoid arthritis ina patient in need thereof comprising administering orally to saidpatient a therapeutically effective amount of a calcitonin in free orsalt form in a dosage range of between 0.4 mg and 2.5 mg and a deliveryagent for calcitonin.
 16. The method according to claim 15, wherein thedosage range is of between 0.6 mg and 1.2 mg.
 17. The method accordingto claim 15, wherein said dose is administered once per day.
 18. Themethod according to claim 15, wherein said dose is administered twice aday. 19-32. (canceled)
 33. A pharmaceutical composition for use in theoral treatment or prevention of Rheumatoid arthritis in a patient inneed thereof, comprising a calcitonin in free or salt form and adelivery agent for calcitonin together with one or more pharmaceuticallyacceptable diluents or carriers therefore.
 34. A pharmaceuticalcomposition according to claim 33, wherein said calcitonin is salmoncalcitonin.
 35. A pharmaceutical composition according to claim 32,wherein the delivery agent is a compound of the following formula I

wherein R¹, R², R³, and R⁴ are independently hydrogen, —OH, —NR⁶R⁷,halogen, C₁-C₄alkyl, or C₁-C₄alkoxy; R⁵ is a substituted orunsubstituted C₂-C₁₆alkylene, substituted or unsubstitutedC₂-C₁₆alkenylene, substituted or unsubstituted C₁-C₁₂alkyl(arylene), orsubstituted or unsubstituted aryl(C₁-C₁₂alkylene); and R⁶ and R⁷ areindependently hydrogen, oxygen, or C₁-C₄ alkyl; and hydrates and alcoholsolvates thereof.
 36. A pharmaceutical composition according to claim35, wherein the delivery agent is a disodium salt, an alcohol solvate ora hydrate of a compound of formula I.
 37. A pharmaceutical compositionaccording to claim 32, wherein the delivery agent is selected from thegroup of 5-CNAC, SNAD, and SNAC and their pharmaceutically acceptablesalts.
 38. A pharmaceutical composition according to claim 32, whereinsaid pharmaceutical composition comprises a delivery agent selected fromthe group consisting of a disodium salt of 5-CNAC, a disodium salt ofSNAD, and a disodium salt of SNAC.
 39. A pharmaceutical compositionaccording to claim 32, wherein said pharmaceutical composition comprisesa delivery agent in micronized form.
 40. A pharmaceutical compositionaccording to claim 39, wherein said micronized delivery agent has anaverage particle size of less than 40, particularly of less than 20,more particularly of less than 10 micrometers.
 41. A pharmaceuticalcomposition according to claim 32 wherein the therapeutically effectiveamount of a calcitonin is delivered orally in a composition comprisingthe calcitonin which is conjugated to a polymer molecule.
 42. Apharmaceutical composition according to claim 32, wherein thetherapeutically effective amount of a calcitonin is delivered with aneffective dosage of an oral pharmaceutical composition comprisingcalcitonin, at least one pharmaceutically acceptable pH-lowering agent,at least one absorption enhancer, and an enteric coating.
 43. Apharmaceutical composition according to claim 32 for preventing ortreating Rheumatoid arthritis in a patient in need thereof comprisingadministering orally to said patient a therapeutically effective amountof a calcitonin in free or salt form in a dosage range of between 0.4 mgand 2.5 mg and a delivery agent for calcitonin.
 44. A pharmaceuticalcomposition according to claim 43, wherein the dosage range is ofbetween 0.6 mg and 1.2 mg.
 45. A pharmaceutical combination for use inthe oral treatment or prevention of Rheumatoid arthritis in a patient inneed thereof, comprising: a. a first agent which is a calcitonin, and b.a co-agent which is selected from the group consisting of salmon, (Asu1-7)-eel or human calcitonin; a calcitonin analogue or derivativethereof; COX-2 inhibitors, e.g. lumiracoxib (Prexige®), celecoxib(Celebrex®), rofecoxib (Vioxx®), valdecoxib (Bextra®), etoricoxib(Arcoxia®); or mixed COX-1 and COX-2 inhibitors, e.g. diclofenac;Etanercept (Enbrel®); pain killers (e.g. Aspirin, Paracetamol); boneformers and bone antiresorbers.
 46. A pharmaceutical combinationaccording to claim 45 comprising between 0.4 and 2.5 mg of a calcitonin.47-48. (canceled)
 49. A method of preventing or treating Rheumatoidarthritis in a patient in need thereof comprising administering to saidpatient an oral pharmaceutical composition comprising between 0.4 and2.5 mg of a calcitonin.